Genetics of behaviour

Behaviour is initiated by the accurate detection and cognitive processing of sensory cues to release an appropriate
emotional, physical or physiological response. This process is greatly influenced by learning and memory; however many
behaviours - such as aggression, parenting, fear and sex - also have an innate component.

The Genetics of behaviour team, headed by Darren Logan, use olfactory-mediated communication in mice as a model system
to identify the genes and neural circuits that underpin behaviour and perception. They generate animals with mutated
genes identified in patients with behavioural, sensory or intellectual disorders to investigate how the genes influence
behaviour and cognition. They also study how sensory cues are perceived and use behavioural, cellular and
transcriptomic techniques to understand how our genes influence our interpretation of the external environment.

Their long-term aim is to understand how learning integrates with innate responses to generate a diversity of
behaviours, and to apply this knowledge to better appreciate how and why behavioural disorders occur.

Background

Behavioural disorders affect more than 25 per cent of people at some point during their lives, but our understanding
of why these disorders arise is limited. This is, in part, because we know little about the basic genetic and neural
pathways that regulate social interaction.

Behaviour results from complex interactions between genetic and environmental components. Every individual has a
unique collection of experiences to draw upon; therefore we each behave slightly differently in a similar situation.
This makes disentangling the genetic components of behaviour in humans challenging.

One way to control for environmental influence is to study behaviours that are highly stereotyped between individuals
and are reproducibly initiated irrespective of prior experience. These, often called instinctive or innate
behaviours, are critical for survival and successful social integration, and are therefore likely to be under a
strong genetic influence. Furthermore, similar innate behaviours are found in many different species, suggesting
there are common underlying neural mechanisms even if the social signals themselves vary significantly.

Mice display a highly stereotyped repertoire of social behaviours that they regulate using olfactory cues. We can
precisely alter the genome, social and odour environment of a mouse, making it an excellent model to identify the
genes and pathways that underpin behaviour.

Research

Our aims

Sensory neurons in the nose express just one olfactory receptor. In this mouse two distinct receptor genes are fluorescently tagged, red and green.

Olfaction, our sense of smell, is mediated by thousands of specialised sensory neurons in the nose. Each neuron
selects just one olfactory receptor gene, or in some cases a few, to express on its surface. Each receptor is
structurally distinct, and therefore recognises a limited set of odours which a mouse will perceive and remember when
the neuron is activated. Some neurons express a sub-class of receptors that detect pheromones, which are specialised
odours emitted by one individual that initiate an innate behavioural response when detected by another.

We use odours and pheromones to elicit learned and innate behaviours in mice, and then we investigate how and why
these responses change in models of human behavioural and cognitive disorders. We are also interested in how natural
genetic variation, and environmental experience, can alter perception of olfactory cues and thus influence responses
to them. Finally, we aim to decode the many different types of olfactory receptor neuron to classify the neural
circuits that underpin behavioural and perceptual responses.

The vomeronasal organ (VNO, blue crescents) in a coronal section of the mouse nose.

Our approach

We employ a range of approaches in our lab. We use genome engineering technologies to ablate candidate genes in mice.
These include genes of unknown function identified by clinical collaborators as potentially being involved in
behavioural, intellectual or cognitive disorders, as well as pheromone and olfactory receptor genes expressed in the
olfactory epithelium and vomeronasal organ that mediate smell.

We examine the resultant mutant mice for both a dysfunction in social and learned behaviours, and for altered neural
activity in response to known pheromones, odours or experience.

In addition, we are using a range of sequencing technologies to identify and assess genomic and transcriptional
variation in the genes that regulate behaviour and perception. Large throughput RNA sequencing at the tissue and
single cell level permits us to delineate very precise neural circuits at the molecular level. This approach sheds
light on how distinct sets of behaviours evolved, are maintained, and are encoded in the genome of different
individuals of the same species.

Research

Gabi Gurria

I studied undergraduate physics at Mexico's National University before moving into the study of hormones and behaviour. For my Ph.D. at Cambridge University I examined the effect of female hormones on social olfactory learning. This was followed by a postdoctoral position at the Babraham Institute, Cambridge, involving research into the neural processing of learning and olfaction. In January, 2011, I joined Sanger's Genetics of Instinctive Behaviour group.

Research

I am coordinating research into the ways in which social cues and pheromones trigger stereotypical instinctive conducts such as aggression or defensive behaviour. I am also studying how the brain detects and processes these olfactory signals, and what genes are involved in these processes.

References

Roles of α- and β-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle.

Establishing clear effects of gender and natural hormonal changes during female ovarian cycles on cognitive function has often proved difficult. Here we have investigated such effects on the formation and long-term (24 h) maintenance of social recognition memory in mice together with the respective involvement of α- and β-estrogen receptors using α- and β-estrogen receptor knockout mice and wildtype controls. Results in wildtype animals showed that while females successfully formed a memory in the context of a habituation/dishabituation paradigm at all stages of their ovarian cycle, only when learning occurred during proestrus (when estrogen levels are highest) was it retained after 24 h. In α-receptor knockout mice (which showed no ovarian cycles) both formation and maintenance of this social recognition memory were impaired, whereas β-receptor knockouts showed no significant deficits and exhibited the same proestrus-dependent retention of memory at 24 h. To investigate possible sex differences, male α- and β-estrogen receptor knockout mice were also tested and showed similar effects to females excepting that α-receptor knockouts had normal memory formation and only exhibited a 24 h retention deficit. This indicates a greater dependence in females on α-receptor expression for memory formation in this task. Since non-specific motivational and attentional aspects of the task were unaffected, our findings suggest a general α-receptor dependent facilitation of memory formation by estrogen as well as an enhanced long-term retention during proestrus. Results are discussed in terms of the differential roles of the two estrogen receptors, the neural substrates involved and putative interactions with oxytocin.

The main olfactory system and social learning in mammals.

There is increasing evidence for specialised processing of social cues in the brain. This review considers how the main olfactory system of mammals is designed to process social odours and the effects of learning in a social context. It focuses mainly on extensive research carried out on offspring, mate or conspecific learning carried out in sheep and rodents. Detailing the roles of the olfactory bulb and its projections, classical neurotransmitters, nitric oxide, oestrogen and neuropeptides such as oxytocin and vasopressin in mediating plasticity changes in the olfactory system arising from these different social learning contexts. The relative simplicity of the organisation of the olfactory system, the speed and robustness of these forms of social learning together with the similarity in brain regions and neurochemical contributions across the different learning paradigms make them important and useful models for investigating general principles of learning and memory in the brain.

Neural encoding of olfactory recognition memory.

Our work with both sheep and mouse models has revealed many of the neural substrates and signalling pathways involved in olfactory recognition memory in the main olfactory system. A distributed neural system is required for initial memory formation and its short-term retention-the olfactory bulb, piriform and entorhinal cortices and hippocampus. Following memory consolidation, after 8 h or so, only the olfactory bulb and piriform cortex appear to be important for effective recall. Similarly, whereas the glutamate-NMDA/AMPA receptor-nitric oxide (NO)-cyclic GMP signalling pathway is important for memory formation it is not involved in recall post-consolidation. Here, within the olfactory bulb, up-regulation of class 1 metabotropic glutamate receptors appears to maintain the enhanced sensitivity at the mitral to granule cell synapses required for effective memory recall. Recently we have investigated whether fluctuating sex hormone levels during the oestrous cycle modulate olfactory recognition memory and the different neural substrates and signalling pathways involved. These studies have used two robust models of social olfactory memory in the mouse which either involve social or non social odours (habituation-dishabituation and social transmission of food preference tasks). In both cases significant improvement of learning retention occurs when original learning takes place during the proestrus phase of the ovarian cycle. This is probably the result of oestrogen changes at this time since transgenic mice lacking functional expression of oestrogen receptors (ERalpha and ERbeta, the two main oestrogen receptor sub-types) have shown problems in social recognition. Therefore, oestrogen appears to act at the level of the olfactory bulb by modulating both noradrenaline and the glutamate/NO signalling pathway.

Ximena Ibarra Soria

I got my bachelor's degree on Genomic Sciences, from the National Autonomous University of Mexico (UNAM). I have a combined background on biology and genetics as well as bioinformatics and maths. During my time at UNAM, I was involved in two main research projects. The aim of the first one was to assess if it was possible to reprogram dopaminergic neurons into neural precursors, and the second one intended a methodology to reliably identify structural variation in personal genomes.

Research

Currently, I am a PhD student in the Genetics of Instinctive Behaviour Group. I am interested in studying the plasticity of the olfactory system in response to a changing environment.

We have entered the era of individual genomic sequencing, and can already see exponential progress in the field. It is of utmost importance to exclude false-positive variants from reported datasets. However, because of the nature of the used algorithms, this task has not been optimized to the required level of precision. This study presents a unique strategy for identifying SNPs, called COIN-VGH, that largely minimizes the presence of false-positives in the generated data. The algorithm was developed using the X-chromosome-specific regions from the previously sequenced genomes of Craig Venter and James Watson. The algorithm is based on the concept that a nucleotide can be individualized if it is analyzed in the context of its surrounding genomic sequence. COIN-VGH consists of defining the most comprehensive set of nucleotide strings of a defined length that map with 100% identity to a unique position within the human reference genome (HRG). Such set is used to retrieve sequence reads from a query genome (QG), allowing the production of a genomic landscape that represents a draft HRG-guided assembly of the QG. This landscape is analyzed for specific signatures that indicate the presence of SNPs. The fidelity of the variation signature was assessed using simulation experiments by virtually altering the HRG at defined positions. Finally, the signature regions identified in the HRG and in the QG reads are aligned and the precise nature and position of the corresponding SNPs are detected. The advantages of COIN-VGH over previous algorithms are discussed.

Proceedings of the National Academy of Sciences of the United States of America2011;108;37;15294-9

Research

I am a Neurobiologist currently in the 6th year of my post-doctoral studies. My research interests lie in the fields of olfaction, brain and behavior. I am particularly interested on how olfactory cues can modulate behavior and emotion, and in the neuronal variability at the single cell level.

Elizabeth Wynn

- Advanced Research Assistant

I did a BSc in Natural Sciences at the University of Bath. After graduating in 2008 I joined the mutant mouse generation team at the Sanger.

Research

I currently work on the Genetics of Instinctive Behaviour project. My main role is developing targeting vectors to knock out receptor clusters in the mouse vomeronasal organ.